It is now universally acknowledged that endothelial dysfunction, an alteration of the normal biochemical processes normally performed by endothelial tissue which causes several vascular disorders and particularly male erectile dysfunction, is due to the reduced local bioavailability of nitric oxide (NO), the quintessential endogenous vasodilatory substance.
Production of nitric oxide occurs starting from a semi-essential amino acid, L-arginine, which is converted into nitric oxide and citrulline by the nitric oxide synthase (NOS) enzyme. There are three isoforms of this enzyme, designated respectively by the acronyms NOS1 (neuronal), NOS2 (inducible) and NOS3 (endothelial).
Nitric oxide, once produced, enters the smooth muscle cell, where it activates a particular enzyme known as soluble guanylyl cyclase (sGC), with a consequent increase in the quantity of intracellular cyclic guanosine monophosphate (cGMP), reduction in the concentration of Ca2+ ion, and consequent vasodilation.
In view of the above, there are three hypothetical ways to act on the decrease in nitric oxide bioavailability: increase the bioavailability of the nitric oxide precursor, i.e., L-arginine; increase the activity of NOS enzymes; and increase the concentration of intracellular cGMP.
The semi-essential amino acid L-arginine is derived mostly from food and only for 5-15% from de novo synthesis. Several metabolic studies have shown that after oral administration, L-arginine is subjected to massive systemic and pre-systemic elimination by intestinal bacteria and by the arginases present in the intestine and liver. A recent experimental study, in which a radioactive isotope of L-arginine was administered, showed that only 1% of the administered dosage is used as a precursor by NOS, mostly due to intense intestinal metabolism. Moreover, it has been demonstrated scientifically that the administration of L-arginine produces blood levels of this amino acid that are characterized by a short half-life, a factor which severely limits the possibility of L-arginine to perform a satisfactory therapeutic effect. Another limitation to oral administration of high doses of L-arginine is the presence of endogenous inhibitors of the reaction for conversion of L-arginine into nitric oxide by NOS. These inhibitors push the activity curve of the enzyme reaction toward higher levels of L-arginine than those administered, an effect acknowledged scientifically as a “paradox effect”.
Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of all three NOS isoforms. ADMA normally circulates in blood at low dosages, but a conspicuous increase thereof is observed in subjects affected by endothelial dysfunction and in particular by erectile dysfunction or in subjects receiving excessive administration of L-arginine. It has been demonstrated scientifically that the ratio between L-arginine and ADMA is one of the key factors in the production of nitric oxide by NOS.
Accordingly, oral administration of L-arginine is unable to increase endogenous production of nitric oxide due to the low absorption of this amino acid caused by: the intense catabolism to which it is subjected in the intestine; its short half-life; and difficulty in modifying the L-arginine/ADMA ratio.
Currently, erectile dysfunction therapy is based substantially on oral administration of phosphodiesterase-5 (PDE5) inhibitors. Drugs containing active ingredients capable of inhibiting PDE5 act by increasing the bioavailability of cGMP at the smooth muscle cell level, inhibiting its catabolism operated by PDE5. However, these drugs are actually unable to increase nitric oxide synthesis and are therefore considered “on demand” drugs, which lead to a temporary increase in erectile functionality.
As an alternative, therapies are being tested for treating erectile dysfunction by direct insertion of the NOS gene at the penile endothelial cell level. This gene therapy procedure uses bacterial vectors to transfer the NOS gene and up to now has proved to be valid in improving erectile function in rats. However, such a method has not yet been developed sufficiently for use in humans; moreover, resorting to gene therapy procedures, and in particular the use of bacterial vectors, is an approach that might be more difficult to accept for a patient with respect to the administration of a drug.
There is, therefore, the need for a drug that can cure endothelial dysfunction and the disorders linked to it by increasing the amount of nitric oxide produced by the body.